Grant: Operating Grant: SickKids-CIHR-IHDCYH New Investigator Grants

This project will examine how impairments in chromatin remodeling complexes lead to altered brain development in childhood disorders like Autism Spectrum Disorder (ASD) and Intellectual Disability (ID). Genetic mutations in protein subunits that compose chromatin remodeling complexes are commonly observed in ASD and ID patients. However, very little is known about how these complexes regulate the expression of genes during brain development, or how loss of chromatin remodeling function leads to the development of cellular and behavioural impairment. I will be working with interdisciplinary collaborators and co-mentors to address this knowledge gap, by investigating the role of a chromatin remodeling complex found only within neurons (nBAF). Genetic mutations in Baf53b, the defining subunit for nBAF, have recently been identified in several ASD and ID patient cases, making Baf53b an ideal target to study the role of chromatin remodeling in brain development and ASD. I have developed and characterized a novel mouse model, that will allow me to specifically examine how loss of Baf53b within excitatory or inhibitory neuronal cells leads to the development of ASD-relevant behaviours, impaired chromatin regulation and gene expression, and altered neuronal and synaptic development. Results will be published in high-impact journals, presented at national and international conferences and disseminated to the broader ASD and ID communities through public lectures and outreach activities. Findings from this work will significantly expand our understanding of the biological mechanisms underlying gene regulation in the brain and provide opportunities for novel therapeutic development across a range of childhood disorders, including ASD, ID, and epilepsy.